Terra Sigillata

Today’s edition of the NCI Cancer Bulletin features another natural product clinical trial, this time for depsipeptide in T-cell lymphoma.

Depsipeptide (Romidepsin or FR901228) is an early histone deacetylase inhibitor isolated from fermentation of Chromobacterium violaceum. Several histone deacetylase inhibitors are in clinical trials for various cancers and many are derived from natural products. However, the first HDAC inhibitor approved by FDA is a synthetic compound, SAHA or vorinostat (Zolinza), also for T-cell lymphoma.

What is it about T-cell lymphoma that attracts the development of HDAC inhibitors??? Hmmm.

Comments

  1. #1 Bill
    May 1, 2007

    What is it about T-cell lymphoma that attracts the development of HDAC inhibitors???

    Blood cell tumors typically require 2-3 fewer molecular events to progress to malignancy, probably in large part because they do not need to acquire invasiveness/vascularization potential. Such tumors are therefore potentially more dependent on the few molecular alterations they have than are more complex tumors. Upregulation or dysregulation of HDAC activity is a common step in many tumorigenic pathways — it’s more or less a generic “pro-proliferative” event, driving cells to replicate.

    So, my guess — and I do mean guess — is that lymphomas are no more likely than other cancers to have HDAC up/dysregulation in their sordid past, but they are more likely to be dependent on it and vulnerable at that single point of inhibitor action.

  2. #2 Bill
    May 1, 2007

    Oops:

    …fewer molecular events than solid tumors to progress…

  3. #3 Bill
    May 1, 2007

    Oops again — HDACs are typically recruited by repressors, not activators. I got HDACs and histone acetyltransferases the wrong way around; I’m always doing that.

    When HDACs are involved in cancer, I think the supposition is that inappropriate deacetylation (silencing) of tumor suppressor genes is involved. So, with that change, I think my guess stands.

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